Melatonin, which is a widely used over-the-counter therapy for the treatment of sleep disorders, is a natural hormone produced and secreted by the pineal gland. It acts at two G-protein coupled receptors (MT1 and MT2), which are negatively coupled to adenylyl cyclase and which play a role in the regulation of sleep and circadian rhythym by controlling neuronal firing in the suprachiasmatic nucleus of the thalamus. Melatonin agonists and partial agonists have the potential to improve sleep quality by resynchronizing the disrupted rhythymicity of sleep/wake cycles.
In addition, melatonin agonists such as agomelatine have been shown to be active in animal models predictive of clinical antidepressant efficacy, such as the Chronic Mild Stress model [Neuropsychopharmacology 28(4), 694 (2003)] and the Forced Swim Test [Journal of Psychiatry and Neuroscience, 29(2), 126 (2004)]. Agomelatine has recently been reported to be active in clinical trials for the treatment of depression [L'Encephale 29(2), 165 (2003) and www.medicalnewstoday.com, Apr. 5, 2005].

The compounds of the present invention have potent affinity for melatonin MT1 and MT2 receptors and are thus useful for controlling sleep disorders and for the treatment of depression. In addition, the compounds of the present invention are capable of being hydrolyzed in vivo (ie, acting as pro-drugs) to agents with potent agonist and partial agonist effects at serotonin 5-HT2C receptors. 5-HT2C agonists represent a novel therapeutic approach toward the treatment of schizophrenia. Several lines of evidence support a role for 5-HT2C receptor agonism as a treatment for schizophrenia. Recent studies have demonstrated that 5-HT2C agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37: 953-955, 1998; Di Matteo, V., et. al., Neuropharmacology 38: 1195-1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine. In contrast, 5-HT2C agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, a recent study demonstrates that 5-HT2C agonists decrease firing in the ventral tegmental area (VTA), but not in substantia nigra Di Matteo and Di Giovanni, op. cit.). The differential effects of 5-HT2C agonists in the mesolimbic pathway relative to the nigrostriatal pathway suggests that 5-HT2C agonists will have limbic selectivity and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
Atypical antipsychotics bind with high affinity to 5-HT2C receptors and function as 5-HT2C receptor antagonists or inverse agonists. Weight gain is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine and it has been suggested that 5-HT2C antagonism is responsible for the increased weight gain. Conversely, stimulation of the 5-HT2C receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., Human Psychopharmacology 10: 385-391, 1995; Rosenzweig-Lipson, S., et. al., ASPET abstract, 2000). As a result, 5-HT2C agonists will be less likely to produce the body weight increases associated with current atypical antipsychotics. Indeed, 5-HT2C agonists are of great interest for the treatment of obesity, a medical disorder characterized by an excess of body fat or adipose tissue and associated with such comorbidities as Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality. Other therapeutic indications for 5-HT2C agonists are obsessive compulsive disorder, depression, panic disorder, sleep disorders, eating disorders and epilepsy.